Very Weak Acid Ionization Constants

CH3COCH2COCH3

CH3NO2

H2O

C2H5OH

CH3COCH3

RCCHRCH=CH2

CH3CH3

CH3COCH-COCH3

CH2–NO2

OH –

C2H5O –

CH3COCH2–

RCCH –

RCH=CH –

CH3CH2 –

ACID CONJ. BASE pKa

9.0

10.2

15.7

15.9

20

2544

50

Weak Acid Ionization Constants

7.1 x 10 –4

4.5 x 10 –4

3.0 x 10 –4

1.7 x 10 –4

8.0 x 10 –5

6.5 x 10 –5

1.8 x 10 –5

4.9 x 10 –10

1.3 x 10 –10

HF

HNO2

C9H8O4 (aspirin)

HCO2H (formic)

C6H8O6 (ascorbic)

C6H5CO2H (benzoic)

CH3CO2H (acetic)

HCN

C6H5OH (Phenol)

F–

NO2 –

C9H7O4 –

HCO2 –

C6H7O6 –

C6H5CO2 –

CH3CO2 –

CN –

C6H5O –

ACID CONJ. BASE Ka pKa=-logKa

3.1

3.3

3.5

3.8

4.1

4.2

4.7

9.3

9.9

Reactions of alcohols.a. Reactions as acids, with metals.

ROH + Mo RO- M+ + H.

M = Na, K, Li, Ca, Al, Mg

ROH reactivity order : CH3OH >1 > 2 > 3

Reactivity of alcohols follows the order of their acidity. The main purpose of this reaction is formation of strong organic bases -

alkoxides.

Reactions of alcohols.b. Reactions as bases. Conversion to alkyl halides.

Mechanism:

ROH + HX ROH2+

SN2X-

RX + OH2

R+ + X-SN1

RX

possible rearrangement

Order of hydrogen halide reactivity :HI > HBr > HCl

Order of ROH reactivity :3 > 2 > 1< CH3OH

Reactions of alcohols.c. With phosphorus trihalides. Conversion to alkyl bromide or

iodide. Note that PI3 is generated in situ.

R-OHP + I2

R-XPBr3

The main intent of this reaction is to convert a bad leaving group (OH, strong base) into a good leaving group (dibromophosphine oxide, weak base, conjugate base of strong halophosphorous acid). A preferred method for generating alkyl halides from alcohols when possible carbocation rearrangement is to be avoided. Usually, 100% inversion of chiral alcohols results.

Reactions of alcohols.d. With thionyl chloride. Conversion to alkyl chloride.

SCl Cl SCl O RR-OH + R3N:

POOR LEAVING GROUP

GOOD LEAVING GROUP

+ R3N+H Cl-

O O

SCl O R

O

Cl-

Cl- + SO 2 + RCl

The main purpose of this reaction is to convert the OH group into a good leaving group (chlorosulfonyl, weak base, conjugate base of very strong chlorosulfurous acid). Likewise, a mild, preferred method for generating alkyl halides from alcohols when possible carbocation rearrangement is to be avoided. Usually, 100% inversion of chiral alcohols results.

Reactions of alcohols.e. Dehydration/formation of ethers. Mechanism :

C

H

C

OH

C

H

C

OH2+

C

H

C C

H

C

OR

C

H

C

OR'

C

H

C

OR

C

H

C

OR'

+ HA

+ HAE2 or E1

A-

SN1 ROH or R'OH

possible rearrangement

+

or

SN2ROH or R'OH

or

Ether formation (i.e. substitution on protonated alcohol) is favored by low (< 180C) temperatures and by the presence of excess alcohol. Elimination is more effective with 3° substrates.

Ethers. A family of molecules with a general formula : R-O-R (symmetrical ethers) or R-O-R' (unsymmetrical ethers). Due to the presence of lone electron pairs on an O atom, this molecules are modestly polar and can serve as acceptors of H-bond. One use of ethers as solvents is to stabilize the metal or organic cations, i.e. diethyl ether (Et2O) used as a solvent in Mg Grignard reaction or tetrahydrofuran (THF) in Li Grignard reaction.

Preparation of ethers. A preferred small scale method for preparation of unsymmetrical ethers is Williamson synthesis:

RO- M+ + R'X R'OR + M+X-

RX reactivity order : CH3 >1 > 2

The choice of placement of alkyl groups (i.e. either on an alkoxide or alkyl halide)is dictated by the need to avoid elimination. Thus 2 or 3 alkyl groups must be parts of an alkoxide anion while the 1 group is used in an alkyl halide.

Epoxides. 3-membered, cyclic ethers are known as epoxides. The simplest epoxide is ethylene oxide or oxirane. They are often

used as the substrates for nucleophilic ring opening .

Preparation of epoxides. a. From alkenes and peroxyacids. The most common method for epoxide synthesis. Usually, m-CPBA (m-chloroperoxybenzoic acid ) is used. Note, that the reaction is concerted and therefore stereospecific and stereoselective.

H

CH3

H3C

H H CH3

H3C H

OO O

C H

O

Ar O

C H

O

Ar

trans-2-butene trans-dimethyloxirane

m-CPBA

Preparation of epoxides. b. From halohydrins, catalyzed by alkoxide anions. Note, that the reaction is concerted and therefore stereospecific and stereoselective.

H CH3

H CH3

OH

Br

RO -

H CH3

H CH3

O -

Br

- Br -

H CH3

H CH3

O

cis-dimethyloxirane

halohydrin

2S,3S-3-bromo-2-butanol

Reactions of epoxides. a. Nucleophilic ring-opening. Also known as base-catalyzed ring-opening. The reaction proceeds by an SN2-like process and the least-hindered carbon is attacked. Only strong bases such as ammonia, alcoholic OH-, alkoxides, cyanides or Gringard reagents are effective. The reaction is stereospecific and diastereoselective.

H3C H

H3C H

O -

CH3O -

H3C H

H3C H

O

OCH3

-H+

H3C H

H3C H

OH

OCH3H3C H

H3C H

O

cis-dimethyl oxirane

rac-1-methoxy-2-propanol

Reactions of epoxides. b. Acid-catalyzed ring-opening. This mode of epoxide ring-opening allows for the use of weaker nucleophiles such as halides, water or alcohols. Unlike the base-catalyzed ring-opening,the attack proceeds at the 3°carbon if the nucleophile is not a halide anion. If the nucleophile is a halide anion, the reaction proceeds at the least-hindered carbon. The reaction is stereospecific and diastereoselective.

H CH3

H3C H

OH

H2O

H CH3

H3C H

O+

H

OH2+

H+ -H+

H CH3

H3C H

OH

OHH CH3

H3C H

O

trans-dimethyloxirane meso-2,3-butanediol

Reactions of alcohols.f. Formation of esters. 1. Formation of esters of sulfonic acids (alkyl sulfonates).

R3N:+ R3N+H Cl-SR' Cl SR' O R

O

O

R-OH +

O

O

POOR LEAVING GROUP GOOD LEAVING GROUP

The main intent of this reaction is to convert a bad leaving group (OH, strong base) into good leaving groups (sulfonyl oxides, weak bases, conjugate bases of very strong sulfonic acids).

Reactions of alcohols.f. Formation of esters. 2. Formation of esters of carboxylic acids.Two ways are predominant: acid-catalyzed formation from carboxylic acids and base-catalyzed formation from carboxylic acid halides. The latter is a preferred, milder method.

R3N:+ R3N+H Cl-

R C

O

OH

+ R'OHH+

R C

O

OR'

+ H2O

R C

O

Cl

+ R'OH R C

O

OR'

CH3CH3

CH4

CH2=CH2

HC CH

CH3X

CH3OH

CH3NH2

+1- 1

- 2

- 4

- 3

+2

H3CO

H

H3CO

CH3

+3

H3CO

OH

CO2

+4

Loss of electrons - OXIDATION

Gain of electrons - REDUCTION

Reactions of alcoholsg. Oxidation reactions. Formation of aldehydes and ketones.

Preparative methods I.

Catalytic hydrogenation (reduction) or metal hydride reduction of carbonyl compounds. These reactions introduce a very importantaspect of the carbonyl group chemistry, a nucleophilic addition to the carbonyl group. In the examples below, this occurs via a hydrideanion. This anion is supplied via a mixture of hydrogen gas and ametal catalyst (Pt, Pd, Ni) at high temperatures and pressures or viasalts called metal hydrides. Keep in mind that catalytic hydrogenation will reduce double bonds, therefore:

Metal hydrides are commonly used. Typically these are either the sodium borohydride (NaBH4) or lithium aluminum hydride (LiAlH4).In these salts, a BH4

- group or a AlH4- group serve as carriers of the

hydride anion. The mechanism of the reaction involves the formation of a tetrahedral intermediate, an alkoxide anion.

O

H3CH 2C H1. NaBH4

2. H2O, H+ CH 3CH 2CH 2OH

i. Preparation of 1° alcohols from aldehydes, esters or carboxylic acids.

O

H3CH 2C H

H-

O -

H3CH 2C HH

2. H2O

H+

1. BH4-

CH 3CH 2CH 2OH

nucleophilic attack on the carbonyl group

ii. Preparation of 2° alcohols from ketones.

O

H3CH 2C CH 31. LiAlH4

2. H2O, H+ CH 3CH 2CHOH CH 3

tetrahedral, alkoxide anion intermediate

Preparative methods II.

Reactions involving Grignard reagents.

(CH3)2CH--Mg+ Br -

Grignard reagents are used as a source of very basic/nucleophiliccarbon. The carbon in a Grignard reagent, being a part of a very polar, covalent C-metal bond, carries partial negative charge. The metals most commonly used are Li or Mg. Various alkyl groups may be utilized, such as 1°, 2° or 3°; vinyl, phenyl etc. In all cases the order of alkyl halide reactivity is :

RI > RBr > RCl

i. Preparation of Mg Grignards: Diethyl ether (Et2O) is used in order to stabilize the Mg cation via unshared (lone-pair) electrons of oxygen.

RX + Mgo

etherMg+ R X-

ii. Preparation of Li Grignards (commonly referred to as alkyl lithiums): THF (tetrahydrofuran, a cyclic ether) is used in order to stabilize the Li atom via unshared (lone-pair) electrons of oxygen.

RX + 2LioTHF

R-Li + Li+ X -

As nucleophiles, Grignard reagents are used to make C-C bonds via nucleophilic opening of epoxides (3-membered cyclic ethers) or nucleophilic addition to the carbonyl group. These are versatile, mild reactions and are the preferred way of alcohol synthesis.

The former proceeds with the formation of the alkoxide anion. The use of an alkoxide anion as a leaving group is possible due to the significant basisity of the Grignard reagents and the relief of the ring strain inherent in the 3-membered epoxide rings. The procedure is used to prepare 1° alcohols, and it extends the carbon framework by 2 carbons.

2. H2O, H+ (CH 3)2CH CH2CH2OH

(CH 3)2CH

O- Mg2+ Br-

HH

2. H2O

H+

nucleophilic opening on the epoxide

alkoxide anion intermediate

O 1. (CH3)2CH-Mg +Br -

H2C CH 2

O (CH 3)2CH CH2CH2OH

Mg+Br -

H3C

H3C

H

H+ (HO)- Mg2+ Br-

The 1° alcohols are also formed from the reaction of 1 mole of a Grignard reagent and methanal (formaldehyde). In this case, the carbon framework is extended by 1 carbon.

O

H H

i. Preparation of 1° alcohols from formaldehyde.

O

H H

O- Mg2+ I-

H3CH 2C HH

2. H2O

H+ CH 3CH 2CH 2OH

nucleophilic attack on the carbonyl group

tetrahedral, alkoxide anion intermediate

CH 3CH 2

Mg +I -

2. H2O, H+ CH 3CH 3CH2OH1. CH3CH 2-Mg +I -

+ (HO)- Mg2+ I-

The 2° alcohols are formed from Grignard reagents and aldehydes with two or more carbons, or formate esters (HCOR). The latter requires 2 moles of a Grignard reagent.

O

(H3C)2C H

ii. Preparation of 2° alcohols from aldehydes or formate esters.

2. H2O, H+ (CH 3)2C CHOH CH 31. CH3-Mg+Cl -

HH

3° alcohols are obtained from Grignard reagents and ketones or esters of carboxylic acids. Again, the latter option requires 2 moles of a Grignard reagent.

O

H3CH2C CH 3

iii. Preparation of 3° alcohols from ketones or esters of carboxylic acids.

2. H2O, H+

1. CH3-Mg+Cl - H3CH2COH

H3CCH 3

O

H3C OCH 2CH 3 2. H2O, H+

1. (CH 3)2CH -Mg+Br - H3COH

(H3C) 2HCCH(CH 3)2